Neuropathic pain is a worldwide health problem with limited treatment options due to gaps in our understanding of the underlying mechanisms of this disorder. Nerve-injury induced neuropathic pain is associated with changes in the expression of channels, proteins, and enzymes within the dorsal root ganglion (DRG). Kv1.2, one subtype of voltage-gated potassium channels (Kv) that are responsible for neuronal hyperpolarization, was found to be down-regulated in the injured DRG following nerve- injury. This down-regulation contributes to neuropathic pain genesis, however, the mechanism of how nerve injury causes DRG Kv1.2 channel down-regulation is still incompletely understood. DNA methylation is an epigenetic mechanism of gene transcription regulation that governs gene expression by interfering with interactions of transcription factors with gene promoter. The promoter of the Kv1.2 gene has the binding motif of Oct-1, a transcriptional activator. We recently found that DNMT3a, one of the enzymes that catalyze methylation at CpG islands in genes, was up-regulated in the injured DRG following spinal nerve ligation (SNL). Our preliminary data strongly suggest that DNMT3a is involved in nerve injury-induced DRG Kv1.2 downregulation and contributes to neuropathic pain. This proposal will determine whether and how nerve injury-induced DRG Kv1.2 down-regulation is triggered by DRG DNMT3a and whether DNMT3a regulates Kv1.2 expression and function, and neuronal excitability in DRG and contributes to neuropathic pain. In Aim 1, we will first examine whether and how DNMT3a contributes to the nerve injury-induced downregulation of Kv1.2 in the injured DRG. We will determine if Kv1.2 reduction is dependent on DNMT3a methylation and decreased Oct 1 binding. In Aim 2, we will observe whether blocking the SNL-induced increase in DRG DNMT3a alters Kv1.2 expression, total Kv current and excitability in DRG neurons and behavioral responses. The proposed studies will provide major conceptual advances in our understanding of the molecular mechanism of neuropathic pain and might open a door for developing new strategies for treating neuropathic pain.